DESCRIPTION: (Adapted from application's abstract) Depression in late life, which carries an increased risk of dementia and brittle response to treatment, is a significant public health care concern. Extensive evidence supports a key role of serotonergic dysfunction in the development of major depression. The well-characterized serotonin type 2A receptors (5HT2A) have been among the sites of prime interest in postmortem human studies and animal models of depression, and an effect of age on the density of this receptor subtype has been observed. We recently used a position emission tomography (PET) to demonstrate a marked reduction in 5-HT2A receptor binding with normal aging in vivo in humans, which is consistent with our hypothesis that age-related changes in serotonergic function may predispose the elderly to depression. However, we have found no effect of depression on the 5HT2a receptor in the elderly. This finding suggests that, although the loss of 5HT2A receptors may contribute to changes in mood and 5HT mediated behaviors, it does not directly account for the development of depression in late life. These observations have prompted investigations of other important components of the 5HT system that are strongly implicated in depression and mechanisms of antidepressant pharmacotherapy. The development of several selective markers of aging, including partial volume correction, have made it possible to image two important targets of action for antidepressant medication: the 5HT1A receptors and the 5HT transporter. This proposal will evaluate the interaction of aging and depression on 5HT1A and 5HTT binding. The interpretation of PET data will be addressed by an MR-based method for Late-Life Mood Disorders at the University of Pittsburgh. Subjects will be longitudinally followed to determine the potential predictive value of serotonergic markers identified by the PET study on treatment resistance and dementia risk.